Pericardial delivery of therapeutic and diagnostic agents

Abstract

A method for treating a patient's heart which comprising delivering a gene therapy agent into the pericardial sac around the patient's heart. The agent is introduced surgically or by transvascular means such as a catheter which has been introduced percutaneously or otherwise. Introducing the gene therapy agent into the pericardial sac contains the agent, allowing high concentration of the agent adjacent large regions of the epicardium and pericardium without spillage or systemic distribution to other organs or tissues. The gene therapy agents of this invention comprise vectors for transferring genetic information to the epicardial cells in vivo or harvested cells which have been genetically engineered in vitro. In a preferred embodiment, a catheter is percutaneously introduced, such as through the femoral artery, and guided upstream into the left ventricle. The distal end of the catheter advanced until it penetrates through the epicardium so that agent can be introduced into the pericardial space. Access to the pericardium may also be gained intraoperatively or through a thoracotomy. Additionally, the method may comprise employing a viscosity enhancer in conjunction with the gene therapy agent to affect the kinetics of the agent-host cell interaction and thus improve the rate and efficiency of transduction.

What is claimed is: 
     
       1. A method for delivering a gene therapy agent to epicardial and pericardial tissue of a patient's heart, comprising: providing an elongated intravascular device having a distal tip configured to pierce a wall of the patient's heart.   guiding the distal tip of the device into the left ventricle of the patient's heart;   piercing the endocardium, the myocardium and the epicardium with the distal tip of the device, said distal tip being located in the pericardial space;   introducing the gene therapy agent through the distal tip; and   maintaining the gene therapy agent within the pericardial space for a sufficient period of time.   
     
     
       2. The method of claim 1, wherein the step of maintaining the gene therapy agent within the pericardial space comprises providing the intravascular device with a helical hypotube distal tip. 
     
     
       3. A method of delivering a gene therapy agent to epicardial and pericardial tissue of a patient's heart, comprising: providing a device configured to be introduced through the patient's chest having a distal tip configured to pierce the pericardium of the patient's heart;   pulling the pericardium away from the epicardium;   piercing the pericardium with the distal tip of the device;   positioning the distal tip of the device in the pericardial space;   introducing the gene therapy agent through the distal tip into the pericardial space; and   maintaining the gene therapy agent within the pericardial space for a sufficient period of time.   
     
     
       4. The method of claim 3, wherein the step of maintaining the gene therapy agent within the pericardial space comprises suturing the pericardium after removing the distal tip. 
     
     
       5. The method of claim 4, wherein the step of maintaining the gene therapy agent within the pericardial space comprises mixing the gene therapy agent with a viscosity modifying component. 
     
     
       6. The method of claim 5, wherein the step of maintaining the gene therapy agent within the pericardial space comprises mixing the gene therapy agent with a viscous biocompatible polyol. 
     
     
       7. A method for genetically modifying cells lining the pericardial space of a patient's heart, comprising delivering a gene therapy agent into the pericardial space defined by the epicardium and the pericardium surrounding the patient's heart thereby transferring DNA to cells lining the pericardial space with the agent. 
     
     
       8. The method of claim 7, wherein the step of delivering the gene therapy agent comprises delivering an agent comprising a vector containing DNA capable of expressing a therapeutically or diagnostically useful protein. 
     
     
       9. The method of claim 8, wherein the step of delivering the gene therapy agent comprises delivering a vector selected from the group consisting of retroviral vectors, adenovirus vectors, adeno-associated virus vectors, herpes simplex virus vectors, semliki forest virus vectors, and sindbis virus vectors. 
     
     
       10. The method of claim 9, wherein the step of delivering the gene therapy agent comprises delivering a vector containing DNA capable of expressing proteins selected from the group consisting of vascular endothelial growth factor, acidic and basic fibroblast growth factors, angiogenin, other angiogenic and vasculogenic factors, nitric oxide synthase, prostaglandin synthase and other prostaglandin synthetic enzymes and superoxide dismutase and other antioxidant proteins. 
     
     
       11. The method of claim 8, wherein the step of delivering the gene therapy agent comprises: a) providing an elongated intravascular device having a distal tip configured to pierce a wall of the patient's heart;   b) guiding the distal tip of the device into a chamber of the patient's heart;   c) piercing the endocardium, the myocardium and the epicardium with the distal tip of the device the distal tip is located in the pericardial space; and   d) introducing the gene therapy agent through the distal tip.   
     
     
       12. A gene therapy method for cells lining the pericardial space of a patient's heart comprising: a) harvesting epicardial or pericardial cells from the heart of a patient;   b) genetically modifying the cells;   c) selecting cells which have been successfully modified;   d) delivering the selected cells into the pericardial space.   
     
     
       13. The method of claim 12 wherein step (b) comprises genetically modifying said cells by introducing into said cells an agent comprising a vector including DNA encoding a therapeutically or diagnostically useful protein. 
     
     
       14. The method of claim 13 wherein said vector is selected from the group consisting of retroviral vectors, adenovirus vectors, Herpes Simplex Virus vectors, Semliki Forest Virus vectors, and Sindbis virus vectors. 
     
     
       15. The method of claim 13 wherein said therapeutically useful protein is selected from the group consisting of vascular endothelial growth factor, acidic fibroblast growth factors, basic fibroblast growth factors, angiogenic factors, vasculogenic factors, nitric oxide synthase, prostaglandin synthetic enzymes, and antioxidant proteins. 
     
     
       16. A method for treating a patient's heart, comprising: combining a gene therapy agent with a first compound, said first compound being a pharmaceutically acceptable carrier, to form thereby a mixture of said gene therapy agent and said first compound;   injecting said mixture of said gene therapy agent and said first compound into the pericardial space of the patient's heart; and   injecting into the pericardial space a second compound to enhance the viscosity of said mixture of said gene therapy agent and said first compound.   
     
     
       17. The method of claim 16 wherein said gene therapy agent comprises a vector including DNA encoding a therapeutically useful protein. 
     
     
       18. The method of claim 17 wherein said vector is selected from the group consisting of retroviral vectors, adenovirus vectors, Herpes Simplex Virus vectors, Semliki Forest Virus vectors, and Sindbis virus vectors. 
     
     
       19. The method of claim 17 wherein said therapeutically useful protein is selected from the group consisting of vascular endothelial growth factor, acidic fibroblast growth factors, basic fibroblast growth factors, angiogenic factors, vasculogenic factors, nitric oxide synthase, prostaglandin synthetic enzymes, and anti-oxidant proteins. 
     
     
       20. The method of claim 16 wherein said second compound is injected simultaneously with said mixture. 
     
     
       21. The method of claim 16 wherein said second compound is injected after the injection of said mixture. 
     
     
       22. A method of treating a patient's heart, comprising: combining a gene therapy agent with (i) a first compound, said first compound being a pharmaceutically acceptable carrier, and (ii) a second compound, said second compound being a viscosity enhancing agent, to form thereby a mixture of said gene therapy agent, said first compound, and said second compound; and   injecting said mixture of said gene therapy agent, said first compound, and said second compound into the pericardial space of the patient's heart.   
     
     
       23. The method of claim 22 wherein said gene therapy agent comprises a vector including DNA encoding a therapeutically useful protein. 
     
     
       24. The method of claim 23 wherein said vector is selected from the group consisting of retroviral vectors, adenovirus vectors, Herpes Simplex Virus vectors, Semliki Forest Virus vectors, and Sindbis virus vectors. 
     
     
       25. The method of claim 23 wherein said therapeutically useful protein is selected from the group consisting of vascular endothelial growth factor, acidic fibroblast growth factors, basic fibroblast growth factors, angiogenic factors, vasculogenic factors, nitric oxide synthase, prostaglandin synthetic enzymes, and anti-oxidant proteins.